This is a competing renewal application requesting support for studies pertaining to the ability of certain drugs of abuse (DOA) to trigger apoptotic neurodegeneration (neuronal suicide) in the developing brain. DOA that we have found can induce developmental neuroapoptosis include those classified as NMDA glutamate antagonists (e.g., phencyclidine), those classified as GABAmimetics (e.g., benzodiazepines and barbiturates), and ethanol (alcohol), which has both NMDA antagonist and GABAmimetic properties. Our findings document that brief exposure to any of these DOA during the developmental period of synaptogenesis triggers widespread neuroapoptosis in the developing rat or mouse brain. The period of synaptogenesis, also known as the brain growth spurt period, in rats and mice occurs during the first two weeks of postnatal life, but in humans, begins in mid-gestation and extends until approximately 3 years after birth. In a recent pilot study we have developed preliminary evidence that in utero exposure of fetal fascicularis monkeys to ethanol triggers a robust neuroapoptosis response in the developing monkey brain. A major thrust of the proposed research is to continue characterizing vulnerability of the fetal monkey brain to DOA-induced neuroapoptosis. In addition, we will conduct studies in mice designed either to supplement and facilitate interpretation of the monkey data, or to address important aspects of DOA-induced neuroapoptosis that cannot readily be studied in monkeys. The mouse research will include an investigation of biochemical mechanisms and gene-regulated pathways by which DOA trigger developmental neuroapoptosis. Public health significance: The developmental neuroapoptosis phenomenon the applicants are studying provides a likely explanation for the neurobehavioral disturbances that alcohol is known to cause (fetal alcohol syndrome) and that other DOA such as phencyclidine are suspected of causing. Learning when during ontogenesis the primate brain is most vulnerable to this neurotoxic process and developing new insight into its underlying mechanisms are important first steps toward establishing public health policies that are more effective in eliminating this source of preventable damage to the developing human brain.